The design of therapeutic strategies to stimulate potent, specific and long-lasting anti-tumor immune responses is a central objective of cancer immunology. Genetic and biochemical characterization of tumor antigens has led to the discovery that most cancer patients mount some form of immune response to developing neoplasms. However, the formation and progression of clinically evident disease implies that endogenous reactions are typically ineffectual. Two features of tumor cell biology contribute to the relatively weak anti-tumor response. First, since tumor cells are derived from normal cells, the immune system may not recognize the tumor cell as dangerous or foreign. Second, tumor cells tend to express a reduced complement of the receptors and molecules that the body relies upon to activate immune responses. Analysis of the mechanisms underlying tumor escape from immune surveillance has underscored inefficient dendritic cell-mediated tumor antigen presentation and negative immune regulation as critical factors that restrain the potency of host responses.
Approaches to stimulating and potentiating anti-tumor immunity that are under active clinical evaluation include cancer vaccines against specific tumor cell antigens or whole tumor cells, monoclonal antibodies, recombinant cytokines and adaptive cellular infusions. Phase I, II and III clinical trials to evaluate these strategies are summarized in Hodi and Dranoff (2006); Laheru and Jaffee (2005); and Finn (2003). Ongoing Phase III clinical trials to evaluate anti-cancer immunotherapy are also described on the National Cancer Institute's clinical trials database at http://cancer.gov/clinicaltrials.
The use of a patient's own tumor cells (autologous cells) to stimulate anti-tumor immunity has been the subject of active investigation for many years. Recent efforts have focused on the development of strategies to augment the efficacy of autologous tumor cell vaccines. A series of papers has uncovered the therapeutic potential of manipulating the cytokine balance within the tumor microenvironment (See, for example, Forni et al., 1988, Cancer and Met. Reviews 7: 289-309; Watanabe et al., 1989, Proc. Natl. Acad. Sci. USA, 86: 9456-9460; Gansbacher et al., 1990, Cancer Res. 50: 7820-7825; Tepper et al., 1990, Cell 60: 503-512; Fearon et al., 1990 Cell 60: 397-403; Colombo et al., 1991, J. Exptl. Med., 173: 889-897; Hock et al., 1991, J. Exptl. Med., 174: 1291-1298; Rollins et al., 1991, Mol. Cell Biol., 11: 3125-3131; Teng et al., 1991, Proc. Natl. Acad. Sci. USA, 88: 3535-3539). Seminal research involving a comparative analysis of the relative abilities of multiple immunostimulatory molecules to enhance host responses following gene transfer into tumor cells identified GM-CSF as the most potent of 33 products tested (Dranoff et al., Proc. Natl. Acad. Sci. USA 90: 3539-3543; U.S. Pat. No. 5,904,920; Dranoff, 2002, Immunol. Rev. 188: 147-154).
The ability of autologous tumor cells that have been engineered to express GM-CSF to stimulate an anti-tumor response human cancer patients has been the subject of a number of clinical trials. A variety of clinical indicators of an anti-tumor response, for example, increased survival time, tumor necrosis, tumor regression, tumor infiltration by CD4+ and CD8+ T lymphocytes, the presence of high titer antibodies against tumor antigens in post-immunization sera, and targeted destruction of tumor vasculature have been reported in clinical trials in patients suffering from metastatic melanoma (Soiffer et al., 1997, Hum. Gene Ther. 8: 111-123; Soiffer et al., 1998, Proc. Natl. Acad. Sci. USA. 95: 13141-13146; Soiffer et al., 2003, J. Clin. Oncol. 21: 3343-3350); non-small cell lung carcinoma (Salgia et al., 2003, J. Clin. Oncol., 21: 624-630; Nemunaitis et al., 2004, J. Natl. Cancer Inst., 96: 326-331); renal cell carcinoma (Simons et al., 1997, Cancer Res., 57: 1537-1546; Tani et al., 2004, Mol. Ther. 10: 799-816.); and prostate carcinoma (Simons et al., 1999, Cancer Res. 59: 5160-5168). The clinical trial results established that autologous tumor cell vaccination consistently improved antitumor immunity in patients with advanced cancers. Nevertheless, because the majority of patients still succumbed to progressive disease, there is a continuing need for effective and potent anti-tumor vaccines.